Preparation of 17alpha-hydroxy steroids



Patented Aug. 11, 1953 PREPARATION OF 17a-HYDROXY STEROIDS Percy L.Julian, Maywood, and Edwin W. Meyer and Isabelle Ryden, Chicago, Ill.,assignors to The Glidden Company, Cleveland, Ohio, a corporation of OhioN Drawing. Ap lication August 4, 1949,

Serial No. 108,658

23 Claims. (Cl. 260239.55)

The present invention relates to the production of l7a-hydroXy-20-ketocompounds in the steroid series.

Many of the cortical hormones possess a 1711- hydroxy group. Thesehormones have been isolated in small quantities by tedious and expensiveextraction and purification methods from adrenal cortices. .Syntheticmethods for introducing the l7a-hydroxy group into steroid materialsobtainable from other material sources have been proposed, Fuchs andReichstein, Helv. Chem. Acta 24, 804, (1941) Hegner and Reichstein,Helv. Chem. Acta. 24, 828, 1941; Sarett, J. Biol. Chem. 162, 601, 1946;Sarett J. A. C. S. 70, 1454, (1948) but such methods as have beenproposed are at best exceedingly involved and expensive.

It appeared that reduction of 16,1'7-oxido-pregnene and pregnanecompounds might lead to the introduction of the l'la-hydroxy group.However, the usual reducing treatments were found to be unsuitable. Itwas then found that the reduction could be effectuated by the use oflithium aluminum hydride. Reduction of 16,17- oxido keto pregnenes andpregnanes with lithium aluminum hydride was found to yield thel7a-hydroxy20-hydroxy compounds as a mixture of the 0-20 epimers. Sinceall of the adre- .nal cortical hormones contain a S-keto group and .mostof them contain a 20-keto group, any prep- :aration beginning with3,17,20-tri-hydroxy compounds must involve an oxidation of suchcompounds. Such an oxidation involves extensive cleavage at the C'17C20bond, producing compounds related to adrenosterone. Thus, for example,Sarett, J. Biol. Chem, 162, 601 (1946), could obtain only an 18% yieldof Kendalls Compound E: on oxidation of Reichsteins CompoundU-2l-monoacetate with chromic acid. Moreover, even if the 20-keto groupis present as such during the oxidation of an hydroxyl group at anotherposition in the molecule of a 17-hydroxysteroid,

"the preparation becomes impractical, either because of cleavage atC17C20 with reagents like chromic acid, or rearrangement of Ring D to aD-homosteroid with reagents of the Oppenauer oxidation type. Ittherefore becomes essential to protect the Czo-keto group during suchtransformations in a way that allows its ready regeneration when suchtransformations have been efiected.

It also follows from the above that it is essential to avoidtransformation of the 20-keto group into a secondary alcohol groupduring any vigorous reduction .1 3 th t f the l6 ,17-oxido group. 7

It is accordingly an object of the present invention to provide aprocess for preparing 17a.- hydroxy-ZO-keto-compounds of the pregnaneand pregnene series.

A further object is to provide a method for converting16,17-oxido-20-keto pregnenes and pregnanes to17a-hydroxy-20-keto-pregnenes and pregnanes.

An additional object is to provide a method for protecting the 20-ketogroup during the reduction of 16,1'7-oxido-20-keto pregnenes andpregnanes with lithium aluminum hydride.

Another object is to produce new steroid compounds useful in theintroduction of a 17:1.- hydroxy group in the pregnenes and pregnanesand in the production of 17w-hydroxy-20-keto steroids. I

Other objects will be apparent from the following description of theinvention.

It has been found that the foregoing objects can be realized byprotection of the 20-keto group of the 16,17-oxido-compounds during thereduction through the formation of a cyclic ketal. It has been foundthat these 16,17-oxido-20-ketals undergo smooth reduction with lithiumaluminum hydride and that the resulting products are readily cleaved tothe l7a-ol-20-ones.

The following examples are illustrative:

EXAIVLPLE 1 Preparation of 16,17-oxido-5-pregnene-3B-ol-20- one acetateA solution of 3.54 grams of A -pregnadiene- 35-ol-20-one acetate in 20ml. of CHC13 was treated at ice bath temperature with a solution of 1.60g. of bromine in 16 ml. of CHC13. The chloroform solution was thenwashed with water, 2% NaOH, water and dried. It was then concentrated invacuo to a white crystalline solid. This solid was dissolved in 50 ml.of benzene and treated with 50 ml. of a benzene solution containing 56mg. of perbenzoic acid per ml. After standing in the dark room at roomtemperature for 24 hours, the benzene solution was washed with 2% NaOHsolution and water. The dried solution was concentrated to a whitecrystalline solid which was debrominated with zinc dust in ether-aceticacid solution. The ether solution was separated from zinc, washed withwater, dilute sodium bicarbonate solution, water and dried. Afterconcentration, the product, A -l6,17-oxidopregnene-3fi-ol-20-oneacetate, was crystallized from methanol; 1.66 g., M. P. 152-155 C.

3 EXAMPLE 2 The preparation of the ketal of 16,17-owido-5-pregnene-iifl-oZ-ZO-one acetate A mixture of 744 mg. of the oxidocompound of Example 1 and 744 mg. of ethylene glycol in 42 ml. ofbenzene was boiled in a flask connected to a modified Bidwell-Sterlingmoisture separator. After the residual moisture had separated from thereaction mixture, 50mg. of p-toluenesulfonic acid monohydrate was addedand boiling continued for three hoursf The mixture was diluted withwater and extracted withether. "The ether solution was washed withdilute sodium carbonate solution, water and dried. After addition ofseveral drops of pyridine,the-solventwas removed in vacuo and the solidresidue crystallized from methanol. There resultedAOO mg. of whiteneedles of the ethylene glycol ketal of 16,17-oxido-5-pregnene-3(3-ol-20-one acetate. The purified material(crystallized from benzene methanol) .melted at 195-197"; [a] 37.8(chloroform).

EXAMPLE 3 Preparation of the ketal of '17a-hydromypregnenolone Asolution of 600 mg. of the ketal of Example '2 in 40 ml. dry etherl ml.benzene was added dropwise with stirring to a suspension of 30.0 mg. oflithium aluminum hydride in 50 ml. of dry ether. The mixture was stirredfor two hours, the last hour while warming gently on a. steam bath. Itwas then decomposed with waterand extracted with ether. The solution waswashed with water, dried and concentrated in vacuo after after theaddition of a drop of pyridine. The remaining solid when crystallizedfrom acetone gave white mealy crystals melting at 178-181".

By recrystallization from acetone, the pure ethylene glycol ketal ofl'ia-hydroxypregnenolone,

.M. P. 185-1872 was obtained [a] 44.8 (chloroform) EXAMPLE 4 Thepreparation of l7a-hydromypregnenolone EXAMPLE The preparation of theketal of 16,17-omidoallopregnane-3p-oZ-20-one acetate A mixture of 1.32g. of 16,17-oXido-allopregnane-3B-ol-20-one acetate and 1.31 g. ofethylene glycol in 50 ml. of benzene containing 50 mg. ofp-toluenesulfonic acid monohydrate was'refiuxed in a flask connected toa Bidwell-Sterling moisture separator. After three hours the solutionwas diluted with ether, washed with water, dilute sodium carbonatesolution, water and dried. The

solvent was removed in vacuo and the residue was crystallized fromacetone containing a few. drops of pyridine. There resulted white,needle-like crystals of the ethylene glycol lieta'l of 16,17-

upon acid .hydrolysis is converted to the l7a-hydroxy-allopregnanolone.

EXAMPLE 6 Alternative preparation of l'la-hydroxypregnenolo-ne The A-16,17-oxido-pregnene-3B-ol-2O-one acetate of Example 1 was hydrolyzedwith methanolic potassium hydroxide to form the 3-hydroxy com- .pound,which'atter several recrystallizations from ether petroleum ether andfrom acetone melted at 189-190 C. This compound was then reacted withethylene glycol as in Example 2 to form the ketal. The ketal of the16,17-oxid-o-5-pregnenei3fi-ol-20-one was then reduced with lithium alu-EXAMPLE '7 The preparation of 17a-hydroxy progesterone A3500-mg. sampleof 16,1'7-0xido-5-pregnene- 3.6-01-20-one was dissolved in 35 ml. oftoluene and 5 ml. of freshly distilled cyclohexanone, and a few ml. ofsolvent distilled to eliminate traces of water. After the addition ofanother 10 ml. of toluene, 250 mg. of aluminum'isopropoxide in 2.5 ml.of toluene was added dropwise to the refluxing solution. After one-halfhour of refluxing, the mixture was decomposed with several drops ofglacial acetic acid in 1 ml. of toluene. The mixture was then steamdistilled, 4 grams of sodium chloride added, and after chilling the finecrystalline solid was separated. Crystallization of this material fromether-petroleum ether gave 330 mg. of product melting at -205 C.Purification by recrystallization from aqueous methanol gave pureT6;l7--oxido-progesterone, M. P. 205-207; -[-a] +160.8. Theoxido-progesterone, upon treatment with ethylene glycol in the presenceof paratolue'ncsulfonic acid, gives the di-lcetal. The

-di-keta'l, upon reduction with lithium aluminum hydride and hydrolysis,yields 17a-hydroxy progesterone of melting point 213-215 C.;

It will be apparent that the Oppenauer oxidation maybe carried outemploying other ketones and catalysts. By Oppenauer oxidation is meantthe conversion of a hydroxy group to a keto group by treatment of thesteroid with aluminum alkoxide in the presence of an excess of ketone.

It will be readily seen from the foregoing examples that a means hasbeen provided for pro- -tectien-of the 20-keto group during thereduction, .as well as during oxidation of the B-hydroxy groups to aketogroup. The invention, moreover,

. is not limited to the particular compounds enumerated, but isapplicable to the treatment of other 16,,17-oXido-20-keto compounds.Where such compounds contain additional keto groups, these may alsobeconverted to cyclic ketal groups, but upon hydrolysis to restore the20-keto group such other keto groups will likewise be restored.Compounds containing .OH groups in positions other than the .3-positionmay also he treated.

Also other aryl sulfonic acid catalysts than .paratoluene sulfonic acidmay be used. Any other suitable method for making the cyclic .ketal maybe used, however. Other glycols than ethylene glycol may also beemployed. Thus, propylene glycol, trimethylene glycol, and the like, maybe used, but preferably the hydroxyl groups should be 1,2 or 1,3 to eachother.

Attention is directed to application Serial No. 93,638, filed May 16,1949, relation to the reduction of 16,17-oxido-20-keto steroids withlithium aluminum hydride; and application Serial No. 108,657, filedAugust 4, 1949, to the oxidation of the 3-hydroxy group of3,17adihydroxy-20- acetals described herein.

Having described the invention, what is claimed is:

1. The process which comprises treating a -20 cyclic lower alkyleneketal of a 16,17-oxido- 20-keto steroid of the C21 series, the nucleusof which is a cyclopentano-10,13-dimethylpolyhydrophenanthrene radicalwith lithium aluminum hydride.

2. The process which comprises treating a C20 cyclic lower alkyleneketal of a 16,17-oxido-20- keto pregnane with lithium aluminum hydride.

3. The process which comprises treating a C-20 cyclic lower alkyleneketal of a 16,17-oxido- 20-keto pregnene with lithium aluminum hydride.

4. The process which comprises reacting a 16,17- oxido-20-keto steroid,the nucleus of which is a cyclopentano 10,13dimethylpolyhy-drophenanthrene radical, with a polyhydric alcohol, twoof the hydroxy groups of which are not farther apart than 1,3 to eachother to form a 20-cyclic lower alkylene ketal, and treating theresulting ketal with lithium aluminum hydride.

5. The process of claim 4 in which the steroid is saturated.

6. The process of claim 4 in which the nucleus of the steroid isunsaturated.

7. The process which comprises treating the 0-20 ethylene ketal of a16,17-oxido-20-keto steroid of the C21 series, the nucleus of which is acyclopentano 10,13 dimethylpolyhydrophenanthrene radical with lithiumaluminum hydride.

8. The process which comprises reacting a 16,17- oxido-20-keto steroidof the C21 series, the nucleus of which is acyclopentano-10,13-dimethylpolyhydrophenanthrene radical with ethyleneglycol to form a cyclic ketal, and reacting the cyclic ketal withlithium aluminum hydride.

9. The process which comprises reacting a 16,17- oxido-ZO-keto steroid,the nucleus of which is a cyclopentano 10,13dimethylpolyhydrophenanthrene radical, with a polyhydric alcohol, two ofthe hydroxy groups of which are not farther apart than 1,3 to each otherto form a 20-cyclic lower alkylene ketal, and treating the resultingketal with lithium aluminum hydride, and then hydrolyzing to restore the20-keto group.

10. The process which comprises reacting 16,17-oxido-5-pregnene-3fi-ol-20-one acetate with ethylene glycol to form acyclic ethylene ketal, treating the cyclic ketal with lithium aluminumhydride, and then hydrolyzing to restore the 20- keto group.

11. The ZO-cyclic lower alkylene ketals of 16,17- oxido-ZO-keto steroidof the C21 series, the nucleus of which is acyclopentano-10,13-dimethy1polyhydrophenanthrene radical.

12. The 20-cyclic lower alkylene ketals of 16,17 oxido-20-ketopregnenes.

13. The 20-cyclic lower alkylene ketals of hydroxy-20-keto steroid ofthe C21 series, the nucleus of which is acyclopentano-10,13-dimethylpolyhydrophenanthrene radical.

14. The 20-cyclic lower alkylene ketals of 17ahydroxy-ZO-keto pregnanes.

15. The 20-cyclic lower alkylene ketals of 17ozhydroxy-20-ketopregnenes.

16. The 20-cyclic ethylene ketal of 5-pregnene- 3,3,17a-C1l01-20-0I16.

17. The 20-cyclic ethylene ketal of 16,17-oxido- S-pregnene-Bp-ol-ZO-oneacetate.

18. The process which comprises treating a 0-20 cyclic ketal of a16,17-oxido-20-keto steroid of the C21 series, the nucleus of which is acyclopentano -10,13- dimethylpolyhydrophenanthrene radical in which thering of the cyclic ketal structure contains more than 2 and less than 5carbon atoms with lithium aluminum hydride.

19. Compounds of the cyclopentano-10,13-dimethylpolyhydrophenanthreneseries possessing in the 17,8-position a substituent of the formulawhere i represents a cyclic ketal structure possessing more than 2 andless than 5 total carbon atoms in the ketal ring, and also possessing anoxygen containing function attached to the 17-carbon atom in the alphaposition by a single bond through the oxygen thereof, said compoundsbeing further characterized in that the sum of the atomic weights of theatoms of said flit-oxygencontaining substituent and the substituents onthe lfi-carbon atom does not exceed the sum of the atomic weights of oneoxygen and three hydrogen atoms, said 16 and 17a-substituents beingcomposed solely of hydrogen and oxygen.

20. The 20-cyclic lower alkylene ketals of 16,17-oxido-allopregnane-3p-ol-20-one 3-acetate.

21. The compounds of claim 20 in which the lower alkylene group is anethylene group.

22. The ZO-cyclic lower alkylene ketals of a1-lopregnane-3,8,17-diol-20-one.

23. The compounds of claim 22 in which the lower alkylene group is anethylene group.

PERCY L. JULIAN. EDWIN W. MEYER. ISABELLE RYDEN.

References Cited in the file of this patent UNITED STATES PATENTS NumberName Date 2,288,854 Stavely July 7, 1942 2,294,433 Westphal Sept. 1,1942 2,302,636 Koster et al. Nov. 17, 1942 2,312,482 Reichstein Mar. 2,1943 FOREIGN PATENTS Number Country Date 876,816 France Nov. 18, 1942OTHER REFERENCES Plattner Helv. Chim. Acta 31, 2210-2214 (1948).

1. THE PROCESS WHICH COMPRISES TREATING A C-20 CYCLIC LOWER ALKYLENEKETAL OF A 16,17-OXIDO20-KETO STEROID OF THE C21 SERIES, THE NUCELUS OFWHICH IS A CYCLOPENTANO-10,13-DIMETHYLPOLYHYDROPHENEANTHRENE RADICALWITH LITHIUM ALUMINUM HYDRIDE.